This invention relates to a new, crystalline substance of Cefditoren pivoxyl and also relates to new processes for the production of the new, crystalline substance of Cefditoren pivoxyl. Cefditoren pivoxyl is an orally administrable pro-drug which belongs to an antibacterially active antibiotic of cephalosporin-type and is a compound usually named as 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester.
Cefditoren is a cephem compound which is represented by the following formula (A): 
and named as (+)-(6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)-ethenyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid. This cephem compound of the generic name xe2x80x9cCefditorenxe2x80x9d is also nominated as 7-[2-methoxyimino-2-(2-aminothiazol-4-yl)acetamido]-3-[2-(4-methylthiazol-5-yl)vinyl]-3-cephem-4-carboxylic acid(syn-isomer, cis-isomer) in Japanese patent No. 1698887(Japanese patent publication xe2x80x9cKokokuxe2x80x9d No. Hei-3-64503 published on Oct. 7, 1991), U.S. Pat. No. 4,839,350 and European patent No. 0175610.
A pivaloyloxymethyl ester of Cefditoren, in which the 4-carboxyl group has been esterified with the pivaloyloxymethyl group for the purpose of enhancing the absorbability of the cephem compound via the digestive tubes upon the oral administration thereof, is such a pro-drug which is known by a generic name xe2x80x9cCefditoren pivoxylxe2x80x9d and is represented by the following formula (B): 
and which has a chemical name xe2x80x9c(xe2x88x92)-(6R,7R)-7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-8-oxo-5-thia-1-azabicyclo-[4.2.0]oct-2-ene-2-carboxylic acid 2,2-dimethylpropionyl-oxymethyl esterxe2x80x9d. Cefditoren pivoxyl is known to be a pale yellow colored and powdery substance having a melting point of 127 to 129xc2x0 C. (see the xe2x80x9cMerck Indexxe2x80x9d, 12th-edition, page 317).
Cefditoren has a low toxicity to mammals but exhibits a very much broad antibacterial spectrum against positive-bacteria and gram-negative bacteria. Cefiditoren pivoxyl is, by itself, antibacterially inactive but is useful as a pro-drug which is adminstrable orally and can be converted into the antibacterially active Cefditoren in the digestive tubes of mammals, with cleaving the ester-forming pivaloyloxymethyl group therefrom. Cefditoren and Cefditoren pivoxyl are known to be a highly excellent therapeutic agent which has extensively been utitilixed for the therapeutic treatments and preventive treatments of bacterial infections caused by a variety of gram-positive bacteria and gram-negative bacteria.
Such products of Cefditoren pivoxyl which are produced and available commercially at present are usually and exclusively in the form of an amorphous and powdery substance. This amorphous substance of Cefditoren pivoxyl is usually prepared by such a method in which a reaction solution containing Cefditoren pivoxyl as synthetized is mixed with isopropyl ether to precipitate an amorphous powder of Cefditoren pivoxyl and this amorphous powder of Cefditoren pivoxyl is dissolved in methanol, and in which the resulting solution of Cefditoren pivoxyl in methanol is added with aqueous isopropanol to precipitate an amorphous powder of Cefditoren pivoxyl and this amorphous powder is then recovered (see, for example, Example 2 of U.S. Pat. No. 4,839,350 and European patent No. 0175610).
Thus, hitherto, any crystalline substance or form of Cefditoren pivoxyl has neither been known nor obtained, as far as we have been aware of. The known, amorphous substance of Cefditoren pivoxyl has widely been utilized as an excellent, antibiotic drug, as stated in the above, but it is not yet a completely satisfactory drug in that it is not stable to a sufficient extent when stored at an elevated temperature and under highly humid conditions. Besides, it has been found that the presently commercially available, amorphous substance of Cefditoren pivoxyl usually has a purity of 94% to 95.5% for the Cefditoren pivoxyl component when analysed by a liguid chromatography on a reverse phase silica gel column as detected with a ultra-violet ray absorption.
Accordingly, there exists an outstanding demand to provide such a new product of Cefditoren pivoxyl which would be much more pure and much more stable than the known, amorphous substance of Cefditoren pivoxyl. There is further presented an another demand to provide such a new process which is able to produce a highly pure product of Cefditoren pivoxyl in an efficient way on a commercial scale.
We, the present inventors, have conducted extensive investigations in order to solve the above-mentioned problems, and we have then presumed that, if Cefditoren pivoxyl can be obtained in a crystalline form, it will be a much more highly pure and stable product.
The present inventors have thus made further investigations in an attempt to produce a crystalline form of Cefditoren pivoxyl. As a result of these further investigations, we have now found that, when an amorphous substance of Cefditoren pivoxyl is once dissolved in an anhydrous, first organic solvent which can dissolve well the amorphous Cefditoren pivoxyl therein, and when the resulting solution of Cefditoren pivoxyl in said first organic solvent is concentrated to a reduced volume of the solution at a temperature of not higher than 15xc2x0 C. by evaporation of the first organic solvent under a reduced pressure, followed by admixing the resultant concentrated solution with a volume of a anhydrous alkanol containing 1 to 5 carbon atoms, as a second organic solvent miscible with the first organic solvent, and then by repeating several times the concentration of the solution and the admixing of the concentrated solution with further amounts of the alkanol of 1 to 5 carbon atoms at a temperature of not higher than 15xc2x0 C., in such an ingenious way as detailed hereinafter, thereby to prepare a concentrated solution containing 50 to 250 mg/ml of Cefditoren pivoxyl dissolved in substantially only one second organic solvent, the alkanol, and when the resultant concentrated solution containing 50 to 250 mg/ml of Cefditoren pivoxyl in the alkanol is subsequently mixed with a volume of water at a temperature of not higher than 10xc2x0 C., then Cefditoren pivoxyl can start to deposit in a crystalline particle form from said concentrated solution and a complete crystallization of Cefditoren pivoxyl can be achieved by agitation of the aqueous mixture of the remaining solution with the deposited crystal particles, at a temperature of 10xc2x0 C. or below, and a crystalline substance of Cefditoren pivoxyl can be separated and harvested from the remaining solution (the liquid phase) by filtration or centrifugation.
Thus, the present inventors, have now succeeded in obtaining such a crystalline substance of Cefditoren pivoxyl which has a high purity of 97% to 98% for the Cefditoren pivoxyl component and can exhibit a remarkably higher storage stability at an elevated temperature, as compared with the known, amorphous substance of Cefditoren povoxyl.
This crystalline substance of Cefditoren pivoxyl now obtained is in the orthorhombic form as measured by an X-ray powder diffractometer and an X-ray single-crystal diffractometer, and said crystalline substance of Cefditoren pivoxyl comprises single crystals having a density of 1.21 to 1.23 g/cm3. This crystalline substance of Cefditoren pivoxyl further has a melting point of 206.2xc2x0 C. to 215.7xc2x0 C. with decomposition, as evaluated from the peak of thermal absorption shown in such a heat flow curve which was determined by testing the crystalline substance in a differential scanning calorimeter. It is considered that this crystalline substance of Cefditoren pivoxyl having the orthorhombic form and having the above-mentioned physico-chemical characteristics should be a novel substance, since any product or substance of Cefditoren pivoxyl which exhibits the above identified particular physico-chemical characteristic was never known in the past.
Furthermore, the present inventors have now found that the new, crystalline substance of Cefditoren pivoxyl now obtained is tasteless to tongue when placed on the tongue, contrarily to that the known amorphous substance of Cefditoren pivoxyl normally gives an objectionably bitter taste to tongue, when it is given orally (see an internationally published specification No. WO 97/13516 of PCT application No. PCT/JP 96/02967).
This invention has now been accomplished on the basis of the above-mentioned findings of the present inventors.
In a first aspect of this invention, therefore, there is provided, as a novel substance, a crystalline substance of Cefditoren pivoxyl, namely 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester, characterized in that said crystalline substance of Cefditoren pivoxyl is of orthorhombic form and has a melting point with decomposition at a temperature in a range of 206.2xc2x0 C. to 215.7xc2x0 C. as evaluated from the peak of thermal absorption shown in the heat flow curve of said substance determined with a differential scanning calorimeter, that a single crystal of said crystalline substance has a density of 1.21 to 1.23 g/cm3 and contains 4 molecules of Cefditoren pivoxyl within a unit lattice of the single crystal, that said crystalline substance has a purity of 97% to 98% for the Cefditoren pivoxyl component as measured by a liquid chromatography with using a reverse phase silca gel column and by detecting with ultra-violet ray absorption, and that said crystalline substance has a higher thermal stability than the known amorphous substance of Cefditoren pivoxyl.
It is preferred that the crystalline substance of Cefditoren pivoxyl has a purity of 97.7% or higher for the Cefditoren pivoxyl component.
Several samples of the new crystalline substance of Cefditoren pivoxyl provided in accordance with the first aspect of this invention were taken and were analysed by an X-ray powder diffractometer, and it is then found that X-ray powder diffractometer data of the tested crystalline substance of Cefditoren pivoxyl shows the diffraction peaks at the following diffraction angles:
approximately 9.7 degree, approximately 10.8 degree, approximately 11.4 degree, approximately 12.1 degree, approximately 13.6 degree, approximately 15.6 degree, approximately 16.2 degree, approximately 17.4 degree, approximately 19.0 degree, approximately 19.5 degree, approximately 20.1 degree, approximately 20.8 degree, approximately 21.5 degree, approximately 25.2 degree, approximately 29.9 degree and approximately 33.0 degree. It is to be added that the known, amorphous substance of Cefditoren pivoxyl does not show any peak of the diffraction when tested by the same X-ray powder diffractometer as above.
Further, a single crystal was taken as a sample from the crystalline product of Cefditoren pivoxyl which was produced in Example 1 given hereinafter, and the crystal structure of this single crystal was investigated using an X-ray single-crystal diffractometer (Model, AFC-5R, a product of Rigaku-Denki Company, Ltd., Japan). As a result, it is found that the tested single crystal of Cefditoren pivoxyl has substantially the crystallographic features as tabulated in Table 1 below.
The above-mentioned crystallographic data of the single crystal of Cefditoren pivoxyl now reveal that one molecule of Cefditoren pivoxyl present in one unit lattice of the crystal takes such a molecular conformation of the molecule as depicted in FIG. 1 of the accompanying drawings. From the above data, it is further revealed that the stereo-chemistry in the oxime moiety and the stero-chemistry at the 3-position of the Cefditoren pivoxyl compound having the crystalline form are evidently of the Z-configuration, and thus are of the syn-configration and of the Z-configuration, respectively, indicating that the crystalline substance of Cefditoren pivoxyl as obtained according to this invention should certainly be a crystalline 7-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-[(Z)-2-(4-methylthiazol-5-yl)ethenyl]-3-cephem-4-carboxylic acid pivaloyloxymethyl ester.
As described hereinbefore, the new, crystalline substance of Cefditoren pivoxyl according to this invention has an improved storage stability than the known amorphous form of Cefditoren pivoxyl.
In order to test the thermal stability on storage of the new crystalline substance of Cefditoren pivoxyl according to this invention, in comparison with the known, amorphous form of Cefditoren pivoxyl, there were employed a sample of the crystalline Cefditoren pivoxyl which was produced in Example 1 given hereinafter, as well as a sample of the amorphous Cefditoren pivoxyl which was produced by admixing a solution of amorphous Cefditoren pivoxyl in methanol with an aqueous iso-propanol to precipitate an amorphous powder of this compound and separating and drying this powder under a reduced pressure. These samples were separately placed in sealed dry containers and were stored for 1 month, for 2 months and for 4 months at 60xc2x0 C. and at 40xc2x0 C., respectively. After these storages, the samples were analysed by a liquid chromatographic method and percentages of the residual quantity of Cefditoren pivoxyl remaining in the stored samples were evaluated from the area under the absorption peak which was shown in the chromatogramms obtained. It is assumed that the initial content of Cefditoren pivoxyl in the test samples was 100% at the starting of the storages.
The test results obtained are summarized in Tables 2 and 3 below.
From the results of Tables 2 and 3 above, it is observed that the crystalline substance of Cefditoren pivoxyl according to this invention is able to have a residual quantity of Cefditoren pivoxyl of 99% even after the 4-month storage at 40xc2x0 C. and also after the 2-month storage at elevated temperatures of up to 60xc2x0 C., indicating that the residual quantity of Cefditoren pivoxyl does not decrease substantially for a long time upon storage of the crystalline Cefditoren pivoxyl under ordinary conditions at ambient temperatures, and that the crystalline Cefditoren pivoxyl of this invention has a better thermal stability than the known, amorphous Cefditoren pivoxyl.
Next, the production of the crystalline substance of Cefditoren pivoxyl according to this invention will be described.
When briefly speaking, the crystalline substance of Cefditoren pivoxyl may be produced by such a process which is characterized by comprising a step of dissolving an amorphous substance of Cefditoren pivoxyl into an anhydrous first organic solvent capable of dissolving Cefditoren pivoxyl well therein than an alkanol of 1 to 5 carbon atoms, and a step of subsequently replacing the first organic solvent component of the resulting solution stepwise by some proportions of an anhydrous alkanol of 1 to 5 carbon atoms as a second organic solvent, in such a manner that the firstly prepared solution of Cefditoren pivoxyl in the first organic solvent is admixed with a proportion of an anhydrous alkanol (the second organic solvent), the resulting admixture is concentrated to a reduced volume by evaporation of the first and second organic solvent therefrom under a reduced pressure, whereby a concentrated solution of Cefditoren pivoxyl in a mixed solvent comprising a smaller proportion of the first organic solvent and a larger proportion of the alkanol (the second organic solvent) is formed, this concentrated solution is again admixed with a further amount of the alkanol and then again concentrated by evaporation of the first and second organic solvents, while the admixing of the concentrated solution with further amount of the alkanol and the concentration of the solution as diluted with the added alkanol are several times repeated, so that there is formed a solution containing at a given concentration of 50 mg-250 mg/ml the Cefditoren pivoxyl dissolved in the solvent solely or substantially solely made of said alkanol, and which process is further characterized by comprising additional step of mixing the latter solution of Cefditoren pivoxyl in the sole alkanol solvent so formed, with a proportion of water at a temperature of not higher than 10xc2x0 C., to make solid particles of Cefditoren pivoxyl to start to deposit in said solution, and a further step of incubating under agitation the solution containing the solid particles so deposited, at a temperature of 0xc2x0 C. to 10xc2x0 C. for a time of 10 minutes to 48 hours so that all the deposited solid particles are crystallized completely in the crystalline form of Cefditoren pivoxyl.
More particularly, in a second aspect of this invention, there is provided a process for the preparation of a crystalline substance of Cefditoren pivoxyl having the orthorhombic form, which comprises conducting successively the following first to eighth steps:
In a first step, dissolving an amorphous substance of Cefditoren pivoxyl in an anhydrous, first organic solvent in which Cefditoren pivoxyl is much more soluble than in an alkanol containing 1 to 5 carbon atoms and which is miscible with the alkanol of 1-5 carbon atoms, thereby to obtain a solution containing 10 mg to 50 mg of the dissolved Cefditoren pivoxyl per 1 ml of the resulting solution of Cefditoren pivoxyl in the first organic solvent,
in a second step, mixing the resulting solution of Cefditoren pivoxyl in the first organic solvent with an anhydrous alkanol containing 1 to 5 carbon atoms as a second organic solvent in such a proportion thereof necessary to reduce the concentration of the Cefditoren pivoxyl dissolved in the resulting mixture of said solution of Cefditoren pivoxyl with the second organic solvent to a concentration of 5 mg to 40 mg of the dissolved Cefditoren pivoxyl per 1 ml of said resulting mixture,
in a third step, concentrating the resulting solution of Cefditoren pivoxyl in the mixed first and second organic solvents as obtained in the second step, at a temperature of xe2x88x925xc2x0 C. to 15xc2x0 C. by evaporation of the organic solvents from said solution under a reduced pressure, to give a concentrated solution containing 50 mg/ml to 250 mg/ml of the dissolved Cefditoren pivoxyl,
in a fourth step, mixing the concentrated solution so obtained in the third step with a further volume of an alkanol of 1 to 5 carbon atoms used as the second organic solvent in such a proportion thereof necessary to reduce the concentration of the Cefditoren pivoxyl dissolved in the resulting mixture of said concentrated solution with the further volume of the alkanol, to a concentration of 25 mg to 125 mg of the dissolved Cefditoren pivoxyl per 1 ml of said resulting mixture,
in a fifth step, concentrating the resulting solution of Cefditore pivoxyl so diluted with the further volume of the alkanol in the fourth step, at a temperature of xe2x88x925xc2x0 C. to 15xc2x0 C. by evaporation of the solvents from said solution under a reduced pressure, to give a concentrated solution containing 50 mg/ml to 250 mg/ml of the Cefditoren pivoxyl dissolved in the solvent entirely or substantially entirely made of said alkanol,
in a sixth step, mixing the concentrated solution obtained in the fifth step gradually with water of a volume of 1-fold to 20-folds greater than the volume of the above concentrated solution at a temperature of 0xc2x0 C. to 10xc2x0 C., to make Cefditoren pivoxyl to start to deposit as crystals,
in a seventh step, agitating the resulting mixture of the above mentioned concentrated solution with water and the deposited crystals as obtained in the sixth step, at a temperature of 0xc2x0 C. to 10xc2x0 C. for a time sufficient to effect a complete crystallization of Cefditoren pivoxyl, and
in an eighth step, separating and harvesting the crystalline Cefditoren pivoxyl from the remaining solution by filtration or centrifugation, followed by drying the harvested crystalline Cefditoren pivoxyl substance under a reduced pressure.
In the process according to the second aspect of this invention, it is preferred that the first organic solvent used in the first step is chosen from ethylene glycol, propylene glycol, acetone, methyl ethyl ketone, methyl iso-butyl ketone, tetrahydrofuran, dioxane, acetonirile, a lower alkyl ester of acetic acid, particularly methyl acetate, ethyl acetate, and n-propyl acetate, methylene chloride and chloroform, as well as mixed solvents of two or more of them, and that the alkanol as the second organic solvent used in the second step and fourth step is chosen from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol, tert-butanol, n-amyl alcohol, iso-amyl alcohol, sec-amyl alcohol and tert-amyl alcohol, as well as mixed solvents of two or more of them.
In the process according to the second aspect of this invention, it is also preferred that the third step and the fifth step of concentrating the solution of Cefditoren pivoxyl in the solvent(s) is conducted at a temperature of 0xc2x0 C. to 10xc2x0 C. under a reduced pressure of 10-50 Torr (guage).
In this process, it is possible that the sixth step of mixing the concentrated solution obtained in the fifth step with water is omitted, but the concentrated solution obtained in the fifth step is immediately agitated at a temperature of 0xc2x0 C. to 10xc2x0 C. for a time sufficient to effect a complete crystallization of Cefditoren pivoxyl, and the resultant crystals are subsequently separated and harvested by filtration or centrifugation and then dried under reduced pressure.
In the seventh step of the process according to the first aspect of this invention, the mixture of the concentrated solution of the dissolved Cefditoren pivoxyl with water and the deposited crystals of Cefditoren pivoxyl which have been produced in the sixth step of the process is agitated at a temperature of 0xc2x0 C. to 10xc2x0 C. for a time sufficient to effect a complete crystallization of Cefditoren pivoxyl. The agitation may be effected by means of a mechanical agitator or under ultra-sonic irradiation. By the term xe2x80x9cto effect a complete crystallization of Cefditoren pivoxylxe2x80x9d is meant that amorphous solid particles of Cefditoren pivoxyl as possibly deposited, if any, can be converted into the crystalline form during the agitation of said mixture so as to prevent a final product of the crystalline Cefditoren pivoxyl from being contaminated with a trace quantity of the amorphous Cefditoren pivoxyl, and also that the Cefditoren pivoxyl solute present in the solution is made deposited to a complete extent or a maximum extent as much as possible.
Once the crystalline substance of Cefditoren pivoxyl has been obtained successfully in accordance with the process of the second aspect of this invention, the crystalline substance of Cefditoren pivoxyl may be produced by a different process which utilizes said crystalline substance of Cefditoren pivoxyl as a seed crystal and comprises some steps of the process of the second aspect of this invention.
In a third aspect of this invention, thus, there is provided a process for the preparation of a crystalline substance of Cefditoren pivoxyl having the orthorhombic form, which comprises conducting successively the following steps (a) to (i):
(a) effecting the process of the second aspect of this invention as described hereinbefore, thereby to obtain a crystalline substance of Cefditoren pivoxyl having the orthorhombic form,
(b) placing the so obtained crystalline substance of Cefditoren pivoxyl as a seed crystal in a solution containing 10 mg/ml to 50 mg/ml of Cefditoren pivoxyl which has been prepared by dissolution of an amorphous substance of Cefditoren pivoxyl in an anhydrous, first organic solvent as defined above,
(c) incubating the solution of Cefditoren pivoxyl in the first organic solvent and further containing therein the seed crystal of Cefditoren pivoxyl added in the above step (b), at a temperature of 0xc2x0 C. to 50xc2x0 C. for a time of 10 minutes to 48 hours, preferably at a temperature of 0xc2x0 C. to 20xc2x0 C. for a time of 20 hours to 40 hours, to make a crystalline substance of Cefditoren pivoxyl to start to deposit from said solution.
(d) concentrating the solution of Cefditoren pivoxyl with the seed crystal so incubated in the above step) (c), at a temperature of xe2x88x925xc2x0 C. to 15xc2x0 C. by evaporation of the first organic solvent therefrom under a reduced pressure, thereby to give a concentrated solution containing 50 mg/ml to 250 mg/ml of the dissolved Cefditoren pivoxyl and the seed crystal of Cefditoren pivoxyl remaining therein,
(e) mixing the concentrated solution of Cefditoren pivoxyl containing the remaining seed crystal as obtained in the above step (d) with an anhydrous alkanol of 1 to 5 carbon atoms as the second organic solvent in a proportion thereof necessary to reduce the concentration of the dissolved Cefditoren pivoxyl to a concentration of 25 mg/ml to 125 mg/ml of the Cefditoren pivoxyl dissolved in the resulting mixture of said concentrated solution of Cefditoren pivoxyl with the alkanol which still contains the remaining seed crystal of Cefditoren pivoxyl,
(f) concentrating the resulting mixture of the concentrated solution of Cefditoren pivoxyl with the alkanol as obtained in the above step (e), at a temperature of xe2x88x925xc2x0 C. to 15xc2x0 C. by evaporation of the first organic solvent and the alkanol therefrom under a reduced pressure, thereby to give a concentrated solution containing the dissolved Cefditoren pivoxyl at its concentration of 50 mg/ml to 250 mg/ml and the remaining seed crystal of Cefditoren pivoxyl,
(g) mixing the concentrated solution comprising the dissolved Cefditoren pivoxyl and the remaining seed crystal as obtained in the above step (f), with water of a volume of 1-fold to 20-folds greater than the volume of said concentrated solution of Cefditoren pivoxyl, at a temperature of 0xc2x0 C. to 10xc2x0 C., thereby to facilitate a crystalline substance of Cefditoren pivoxyl to deposit from the resulting mixture of said concentrated solution of Cefditoren pivoxyl with water,
(h) agitating the resulting aqueous mixture of the solution containing the dissolved Cefditoren pivoxyl, water and the deposited crystalline substance of Cefditoren pivoxyl as obtained in the above step (g), at a temperature of 0xc2x0 C. to 10xc2x0 C., for a time of 20 hours to 40 hours, thereby to effect a complete crystallization of the Cefditoren pivoxyl, and
(i) separating and harvesting the crystals obtained in the above step (h), from the remaining solution, followed by drying the harvested crystals under a reduced pressure.
In the process according to the third aspect of this invention, it is preferred that the solution of Cefditoren pivoxyl in the anhydrous first organic solvent to be added with the seed crystal of Cefditoren pivoxyl in the step (b) is such solution that has been prepared by dissolution of the amorphous substance of Cefditoren pivoxyl in an organic solvent chosen from ethylene glycol, propylene glycol, acetone, methyl ethyl ketone, methyl iso-butyl ketone, tetrahydrofuran, dioxane, acetonirile, a lower alkyl ester of acetic acid, particularly methyl acetate, ethyl acetate, and n-propyl acetate, methylene chloride and chloroform, as well as mixed solvents of two or more of them, and that the alkanol used in the step (e) is chosen from methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol, tert-butanol, n-amyl alcohol, iso-amyl alcohol, sec-amyl alcohol and tert-amyl alcohol, as well as mixed solvents of two or more of them.
In this process, it is also preferred that the step (c) of incubating the solution of Cefditoren pivoxyl containing the seed crystal, as well as the steps (d) and (f) of concentrating the solution of Cefditoren pivoxyl are effected at a temperature of not higher than 10xc2x0 C.
The crystalline substance of Cefditoren pivoxyl according to the first aspect of this invention may be produced also by another process which comprises much more reduced steps than in the processes of the second and third aspects of this invention, with utilizing as a seed crystal such a crystalline Cefditoren pivoxyl as prepared previously.
In a fourth aspect of this invention, there is provided a process for the preparation of a crystalline substance of Cefditoren pivoxyl having the orthorhombic form, which comprises consecutively conducting the following steps (i) to (iv):
(i) a step of effecting the process of the first aspect invention, thereby to obtain a crystalline substance of Cefditoren pivoxyl having the orthorhombic form,
(ii) a step of placing the crystalline substance of Cefditoren pivoxyl obtained in the step (i), as a seed crystal in a solution of Cefditoren pivoxyl which has been prepared by dissolution of an amorphous substance of Cefditoren pivoxyl to a concentration of 10 mg/ml to 50 mg/ml in an anhydrous organic solvent chosen from ethylene glycol, propylene glycol, acetone, methyl ethyl ketone, methyl iso-butyl ketone, tetrahydrofuran, dioxane, acetonirile, a lower alkyl ester of acetic acid, particularly methyl acetate, ethyl acetate, and n-propyl acetate, methylene chloride, chloroform, and mixed solvents of two or more of them, as well as methanol, ethanol, n-propanol, iso-propanol, n-butanol, iso-butanol, sec-butanol, tert-butanol, n-amyl alcohol, iso-amyl alcohol, sec-amyl alcohol, tert-amyl alcohol, and mixed solvents of two or more of them.
(iii) a step of agitating the resulting mixture of the solution of Cefditoren pivoxyl in the organic solvent with the seed crystal of Cefditoren pivoxyl as obtained in the step (ii), at a temperature of not higher than 50xc2x0 C., for a time sufficient to facilitate the crystallization of the Cefditoren pivoxyl in the solution, and
(iv) separating and harvesting the deposited crystalline substance of Cefditoren pivoxyl from the remaining solution by filtration or centrifugation, followed by drying the harvested crystals of Cefditoren pivoxyl under a reduced pressure.